Congenital Deafness

While acquired deafness associated with age or noise exposure
is more common than genetic deafness by roughly 2 orders of magnitude, congenital
deafness occurs in 1 per every 1000-2000 births with autosomal recessive inheritance
being the most common form (more than 75%). Approximately 50% of this hearing loss is genetic, 25% acquired, and 25% of unknown cause.

Abnormalities
of the inner ear such as the Mondini malformation, with variable inheritance patterns, account for roughly 20% of
congenital sensorineural deafness. The bulk of the remaining genetic deafness
is non-syndromic, meaning that it does not have any obvious distinguishing features.

Most of these disorders have been documented with genetic mapping. For this to work there must be more than 10 affected members in a family. Marker analysis enables identification of the region of the genome where the disease gene lies.

Of children with sensorineural hearing loss of any type, between 11-41% of them have inner abnormalities seen on CT. In children who are deemed likely to have an inner ear abnormality and who are sent for MRI scan, about 40% have abnormalities (McClay et al, 2008). Of course, this does not mean that 40% of all deaf children will have MRI abnormalties, but rather 40% of those who are thought by their doctors to have an MRI abnormality, and who are sent for an MRI, have MRI abnormalities. In other words, it means that the abnormal rate for clinicians at the location where this study was done (Dallas), is about 40%.

INHERITED CONGENITAL DEAFNESS

Before we start talking about individual syndromes, inherited deafness is usually symmetrical and bilateral, nearly always sensorineural, and usually more severe at high frequencies. However, a particular pattern of hearing loss called the "cookie bite", generally suggests a genetic pattern -- in other words, it is a fairly specific sign of a genetic deafness pattern. About 2/3 of persons with cookie bite patterns had hereditary hearing loss in a study of one academic practice (Shah and Blevins, 2005). It seems likely that outside of academic settings, cookie-bite hearing patterns are even more likely to be associated with inherited hearing loss.

Non-syndromic (80% of genetic deafness):

About 80% of genetic hearing loss is non-syndromic. Between 1992 and 2001,
38 loci for autosomal dominant nonsyndromic deafness have been mapped and 11
genes have been cloned. Autosomal dominant locii are called DFNA, autosomal
recessive as DFNB, and X-linked as DFN. An update on current locii can be found
on the hereditary hearing loss
homepage, which is hosted by the University of Iowa. Non-syndromic deafness
is highly heterogeneous but mutations in the connexin-26 molecule (gap junction
protein, gene GJB2) account for about 49% of patients with non-syndromic deafness
and about 37% of sporadic cases.

Assays for connexin-26 are commercially available
at several laboratories. About 1 in 31 individuals
of European extraction are likely carriers. However, population analysis suggests
that there are over 100 genes involved in non-syndromic hearing impairment (Morton,
1991). One mutation is particularly common, namely the 30delG.

There is a nomenclature for the nonsyndromic deafness:

Autosomal dominant (DFNA)

Autosomal dominant deafness is passed directly through generations. It is often
possible to identify an autosomal dominant pattern through simple inspection
of the family tree. Examples of autosomal dominant deafness are missense mutation
in COL11A2 (DFNA13) (Leenheer et al, 2001). COL11A2 encodes a chain of type
XI collagen. As an example of a deafness phenotype, in DFNA10 results in a postlingual,
initially progressive, and resulting, without the influence of presbycusis,
in largely stable, flat sensorineural deafness (De Leenheer et al, 2001). DFNA9/COCH
may initially resemble Meniere's
disease, but it progresses and culminates in severe deafness and vestibular
loss.(Lemaire et al. 2003)

Autosomal Recessive (DFNB)

Autosomal recessive disorders require a gene from both the mother and father.

DFNB1 (connexin 26) is the most common form of genetic hearing loss. It presents as prelingual deafness, sometimes with mild-to-moderate hearing loss. There are no vestibular or radiographic abnormalities. It is caused by a mutation in the gap junction protein. There is a 3% carrier rate in the US.

Syndromic deafness (The remaining 20% of congenital deafness)

These are an immensely complicated interlinked set of disorders. The descriptions
here are only to give the general flavor of the diseases and are not meant to
include all features of the disorders. In most cases an OMIM database link to
the main type of the genetic disorder is provided.

Alport
syndrome

Alport syndrome is caused by mutations in COL4A3, COL4A4 or COL4A5. The classic
phenotype is renal failure and progressive sensorineural deafness.

Barakat Syndrome (text courtesy of Dr. Barakat).

Barakat syndrome, also known as HDR syndrome, is an inherited condition characterized by hypoparathyroidism, sensorineural deafness and renal disease (Barakat et al in 1977). Patients usually present with hypocalcaemia, tetany, or afebrile convulsions at any age. Hearing loss is usually bilateral and may range from mild to profound impairment. Renal disease includes nephrotic syndrome, renal dysplasia, hypoplasia or aplasia, chronic renal failure, hematuria, proteinuria and others. The frequency is unknown, but the disease is considered to be very rare.

The defect is on chromosome 10p (Gene Map Locus: 10p15, 10p15.1-p14), with haploinsufficiency or mutation of the GATA3 gene being the underlying cause. Inheritance is probably autosomal dominant. Management consists of treating the clinical abnormalities at the time of presentation. Prognosis depends on the severity of the renal disease.

Branchio-Oto-Renal
Syndrome

Branchio-oto-renal syndrome is caused by mutations in EYA1, a gene of 16 exons
within a genomic interval of 156 kB. This syndrome is characterized by hearing
disturbances and cataract, branchial cleft fistulae, and preauricular pits.
Mondini malformations and related dysplasias may occur.

X-linked Charcot Marie Tooth (CMT)

The dominantly iherited form of X-linked CMT is caused by a mutation in the
connexin 32 gene mapped to the Xq13 locus. Usual clinical signs consist of a
peripheral neuropathy combined with foot problems and "champagne bottle"
calves. Sensorineural deafness occurs in some. (Stojkovic and others, 1999).

As noted above, the connexin gene is also associated with a large percentage
of cases of non-syndromic deafness. There are several other associated neuropathies
and deafness syndromes. Autosomal recessive demyelinating neuropathy, autosomal
dominant hereditary neuropathies type I and II, and X-linked hereditary axonal
neuropathies with mental retardation are all associated with deafness (Stojkovic
and others, 1999).

Goldenhar's syndrome.

Oculoauriculovertebral dysplasia (OAVD) or Goldenhar's syndrome was originally
described in 1881. It includes a complex of features including hemifacial microtia,
otomandibar dysostosis, epibulbar lipodermoids, coloboma, and vertebral anomalies
that stem from developmental vascular and genetic field aberrations. It has
diverse etiologies and is not attributed to a single genetic locus. The incidence
is roughly 1 in 45,000. (Scholtz et al, 2001).

Jervell
and Lange-Nielsen Syndrome

This hearing syndrome is associated with cardiac arrhythmias. There is prolongation
of the QT interval, torsade de pointe arrhythmias (turning of the points, in
reference to the apparent alternating positive and negative QRS complexes),
sudden syncopal episodes, and severe-to-profound sensorineural hearing loss.

Klippel-Feil.

Klippel-Feil (KFS) is a congenital anomaly of the cervical (neck) vertebrae. It manifests as a short neck, low hair line and limited neck mobility. It is associated with congenital anomalies of all three parts of the ear (external, middle and inner ear) as well as the IAC and vestibular aqueduct (see below). According to Yildirim et al (2008), about 60% of KFS patients have ear anomalies. There was no correlation between ear pathology and skeletal or extraskeletal anomalies.

In the "Large Vestibular Aqueduct syndrome" there is enlargement of the endolymphatic duct (ED on figure above) that connects the endolymphatic compartment (blue above) to the endolymphatic sac (which lies just under the dura of the posterior fossa, ES above). See the page EVA on this condition.

Mohr-Tranebjaerg
syndrome (DFN-1)

Mohr-Tranebjaerg syndrome (DFN-1) is an X-linked recessive syndromic hearing
loss characterized by postlingual sensorineural deafness in childhood followed
by progressive dystonia, spasticity, dysphagia and optic atrophy. The syndrome
is caused by a mutation thought to result in mitochondrial dysfunction. It resembles
a spinocerebellar degeneration called Fredreich's
ataxia which also may exhibit sensorineural hearing loss, ataxia and optic
atrophy. The cardiomyopathy characteristic of Freidreichs is not seen in Mohr-Tranebjaerg.

Norrie
Disease.

Classic features include specific ocular symptoms (pseudotumor of the retina,
retinal hyperplasia, hypoplasia and necrosis of the inner layer of the retina,
cataracts, phthisis bulbi), progressive sensorineural hearing loss, and mental
disturbance, although less than one-half of patients are hearing impaired or
mentally retarded.

Pendred
Syndrome

Pendred syndrome is one of the most common syndromic forms of deafness. In essence it is deafness associated with thyroid disease (euthyroid goiter). Vestibular
testing, especially rotatory testing if available, should be obtained in
cases with known mutations. This is due to a mutation in the sulfate ion transporter, 7q31. It is autosomal recessive. Pendred is associated with large vestibular aqueduct syndrome (see above) as well as Mondini (see below). Note that many persons with thyroid problems have Meniere's disease (Brenner et al, 2004), and thus LVAS, Meniere's and Pendred syndrome may all be interconnected.

About 60% of mutations in the SLC26A4 gene known to cause Pendred syndrome can be detected with genetic testing. This is an option in persons who have appropriate symptoms or radiology.

Spinal muscular atrophy (SMA) and hearing symptoms.

Although the SMA's are not generally associated with hearing symptoms, a recent report suggests that the disorder caused by a mutation in TRPV4 can induce a neuropathy as well as hearing loss (Oonk et al, 2014).

Stickler
syndrome.

Mutations in COL11 are the cause in Stickler syndrome. This syndrome is characterized
by hearing impairment, midface hypoplasia, progressive myopia in the first year
of life and arthropathy.

Treacher
Collins Syndrome (OMIM Entry TCOF1)

Treacher Collins syndrome is characterized by coloboma of the lower eyelid
(the upper eyelid is involved in Goldenhar syndrome), micrognathia, microtia,
hypoplasia of the zygomatic arches, macrostomia, and inferior displacement of
the lateral canthi with respect to the medial canthi.

Turner Sydrome.

Turner syndrome occurs in about 1/2000 female births. Most persons with Turner syndrome have but a single copy of the X chromosome and no Y. Roughly two thirds of the Turner's population has hearing loss, about evenly split between sensorineural and conductive types (Ingeborg et al, 2005).

Waardenburg
syndromes type I and II

The clinical signs of Waardenburg Syndrome (WS) include lateral displacement
of the inner canthus of each eye, pigmentary abnormalities of hair, iris, and
skin (often white forelock and heterochromia iridis -- see above), and sensorineural deafness.
The combination of WS type I characteristics with upper limb abnormalities has
been called Klein-Waardenburg syndrome or WS type III. The combination of recessively
inherited WS type II characteristics with Hirschsprung disease has been called
Waardenburg-Shah syndrome or WS type IV.

Ushers
syndrome. -- the most common cause of deafness and blindness together

Usher syndrome is characterised by hearing impairment and retinitis pigmentosa.
Usher syndrome can be classified into 3 different types on the basis of clinical
findings. In recent years it has been found that Usher's genes are somewhat common - -about 1/70 people have a single mutation. In type one, there is both hearing impairment and vestibular impairment.
In type II, there is hearing impairment without vestibular impairment. In type
three, there is variable amounts of vestibular impairment. Ushers patients may
benefit from a cochlear implant. The electroretinogram is generally required
to obtain a clear diagnosis (Loundon et al, 2003). Vestibular
testing should be obtained if possible in Usher's.

Mitochondrial disorders.

Variable inheritance congenital deafness

Wolfram Syndrome, first described in 1938, is also known as DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, deafness). According to Plantinga et al (2008), all patients had similar sensorineural hearing loss with a gently downsloping pattern. It does not progress with age.

Non-Inherited Congenital Deafness

These types of abnormalities account for roughly 20% of congenital deafness,
the remainder being genetic in origin. In general, these disorders can be associated
with genetic disorders, but more often occur independently.

Viral syndromes

Congenital hearing loss is often attributed to prenatal infections with neurotrophic
viruses such as measles or cytomegalovirus (CMV). A recent study suggested that
"more than 40% of deafness of unknown cause, needing rehabilitation"
is attributed to CMV. (Barbi et al, 2003). CMV is the most common intrauterine infection in the United States. Infants can be exposed through breast milk. Other bodily fluids can also transmit CMV (e.g. urine, saliva). In developed countries, older individuals become exposed through secondary mechanisms.

Delayed onset of hearing loss is common -- infants with CMV and normal hearing at birth should be monitored for 6 years. Newborn infants with CMV can be treated with ganciclovir. This treatment must be monitored very carefully as 2/3 of infants develop neutropenia.

The normal cochlea has two and one-half turns. A cochlear malformation consists
of a membranous abnormality, a bony abnormality, or a combination of these
two. If cochlear development is arrested in the embryo, a common cavity may
occur instead of the snail like cochlea. A complete labyrinthine and cochlelar
aplasia is called the Michel deformity (see figure on right, from Strome).

An incomplete partition is called the
Mondini dysplasia or malformation. This furthermore consists of a cystic apex,
a dilated vestibule and a large vestibular aqueduct.

Patients with the common Down's syndrome (Trisomy 21), often have inner ear malformations.

Deformities of the membranous labyrinth -- Schiebe and Alexander

There are also some deformities of the membranous labyrinth -- as for example the very common Schiebe deformity (pars inferior -- cochlea and saccule).

Alexander aplasia is characterized by aplasia of the cochlear duct. The organ of Corti, particularly the basal turn of the cochlea and adjacent ganglion cells, is affected most prominently. Hearing loss is most notable with higher frequencies, while low-frequency hearing is relatively preserved.

The frequency of these disorders mainly comes from temporal bone autopsies. Ther reason is that these deformities cannot be diagnosed on CT scan, as CT scans are not able to define abnormalities of the membranous labyrinth. High-resolution MRI has been used to visualize these structures. Practically
however, conventional 1.5 tesla MRI scanners do not
provide enough detail to be of much clinical value. The newer 3.0 tesla scanners may be of greater value.

One would think that the VEMP test would be a good method of detecting the Schiebe deformity, as the VEMP is sensitive to saccule disturbances.

Malformations of the internal auditory meatus.

Unusually sized openings between the inner ear and the brain (internal auditory meatus) are usually associated with other bone abnormalities (surprise !). Li et al (2014).